CN108892639B - Efficient and environment-friendly method for preparing quinolone compounds - Google Patents

Efficient and environment-friendly method for preparing quinolone compounds Download PDF

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CN108892639B
CN108892639B CN201810918488.4A CN201810918488A CN108892639B CN 108892639 B CN108892639 B CN 108892639B CN 201810918488 A CN201810918488 A CN 201810918488A CN 108892639 B CN108892639 B CN 108892639B
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CN108892639A (en
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黄超
白海瑞
袁明龙
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Yunnan Minzu University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

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Abstract

The invention discloses a method for preparing quinolone compounds in an efficient and environment-friendly manner. The ethyl fluorobenzoylacetate, triethyl orthoformate and amine compound are used as raw materials, and the quinolone compound is synthesized by reacting for 24 hours at the temperature of 130 ℃ under the conditions of no solvent and no catalyst. Meanwhile, after the reaction is finished, ethyl acetate, petroleum ether and methanol are used for washing through decompression and suction filtration, and the purity of the product can reach more than 98.9%. The quinolone synthesis process provided by the invention is simple, convenient to operate, high in yield, green and environment-friendly. The preparation method for efficiently and environmentally synthesizing the quinolone compound provided by the invention has the advantages that the dicarbonyl compound, the triethyl orthoformate and the amine compound which are simple and easy to obtain are fed together, the raw material cost is reduced, no solvent or catalyst is used in the reaction process, and the problems of high pollution, high operation difficulty and the like of an original route are fundamentally solved.

Description

Efficient and environment-friendly method for preparing quinolone compounds
Technical Field
The invention belongs to the technical field of chemical industry, and particularly relates to a method for efficiently and environmentally preparing quinolone compounds.
Background
The quinolone compounds can be used as core modules of various medicines due to the biological activities of antimitotic, anticancer, antimalarial, antibacterial, antiviral, antidiabetic, HIV-resistant and anti-inflammatory. For example, it is a compound which has been used as a clinical therapeutic drug such as sarafloxacin, norfloxacin, pazufloxacin, antofloxacin, praloxacin, delafloxacin, and eltamivir.
Figure 703808DEST_PATH_IMAGE002
Structural representation of quinolone drugs
The synthesis method of the medicine is mostly based on Conrad Limpach, Gould Jacobs, Grohe Heitzer reaction and the like. However, the reaction path is complicated, the steps are long, the raw material cost is high, and the three wastes generated in the production process cause serious environmental pollution, so that the price of the novel quinolone medicaments is high and the damage of the production process to the environment is irreversible. If unnecessary links in the production process can be reduced, the price of synthesizing quinolone medicaments can be reduced, and the pollution to the environment is reduced.
Disclosure of Invention
The invention aims to provide a method for preparing quinolone compounds in an efficient and environment-friendly manner.
The invention is realized by using dicarbonyl compound, triethyl orthoformate and amine compound as raw materials and simultaneously undergoing condensation reaction, substitution reaction and SN2The nucleophilic aromatic substitution reaction is prepared by the following reaction principle:
Figure DEST_PATH_IMAGE004
the preparation method for efficiently and environmentally preparing the quinolone compound, disclosed by the invention, has the advantages that the raw material cost is reduced by feeding the dicarbonyl compound, the triethyl orthoformate and the amine compound which are simple and easy to obtain together, and no solvent or catalyst is used in the reaction process, so that the problems of high pollution, high operation difficulty and the like of an original route are fundamentally solved.
The beneficial effects of the invention are mainly embodied as follows:
1. the raw materials are simple and can be bought in the market with low price;
2. three components of raw materials are fed together for one-pot operation, the intermediate does not need to be separated, and the reaction process is efficient and labor-saving;
3. the whole conversion process is efficient, and the high-end product can be simply washed without chromatographic treatment to obtain a pure compound;
4. safe reaction process, only ethyl acetate and methanol are needed for washing after post-treatment without column separation, and the eluent can be recycled to prevent pollution;
5. the green reaction process, the byproduct is only ethanol, and the atom economy is high;
6. the carbostyril compound has high practical value and is an important composition structure of the antibacterial drug.
Drawings
FIG. 1 is a nuclear magnetic spectrum of Compound No. 1 in example 1 of the present invention;
FIG. 2 is a nuclear magnetic spectrum of Compound No. 2 in example 1 of the present invention;
FIG. 3 is a nuclear magnetic spectrum of Compound No. 3 in example 1 of the present invention;
FIG. 4 is a nuclear magnetic spectrum of Compound No. 4 in example 1 of the present invention;
FIG. 5 is a nuclear magnetic spectrum of Compound No. 5 in example 1 of the present invention;
FIG. 6 is a nuclear magnetic spectrum of Compound No. 6 in example 1 of the present invention;
FIG. 7 is a nuclear magnetic spectrum of Compound No. 7 in example 1 of the present invention;
FIG. 8 is a nuclear magnetic spectrum of Compound No. 8 in example 1 of the present invention;
FIG. 9 is a nuclear magnetic spectrum of Compound No. 9 in example 1 of the present invention;
FIG. 10 is a nuclear magnetic spectrum of Compound No. 10 in example 1 of the present invention;
FIG. 11 is a nuclear magnetic spectrum of Compound No. 11 in example 1 of the present invention;
FIG. 12 is a nuclear magnetic spectrum of Compound No. 12 in example 1 of the present invention;
FIG. 13 is a nuclear magnetic spectrum of Compound No. 13 in example 1 of the present invention;
FIG. 14 is a nuclear magnetic spectrum of Compound No. 1 in example 2 of the present invention;
FIG. 15 is a nuclear magnetic spectrum of Compound No. 2 in example 2 of the present invention;
FIG. 16 is a nuclear magnetic spectrum of Compound No. 3 in example 2 of the present invention.
Detailed Description
The present invention is further illustrated by the following examples and the accompanying drawings, but the present invention is not limited thereto in any way, and any modifications or alterations based on the teaching of the present invention are within the scope of the present invention.
The method for preparing the quinolone compound in an efficient and environment-friendly way takes a dicarbonyl compound, triethyl orthoformate and an amine compound as raw materials, and simultaneously undergoes a condensation reaction, a substitution reaction and SN2The nucleophilic aromatic substitution reaction is prepared by the following reaction principle:
Figure DEST_PATH_IMAGE006
the molar ratio of the dicarbonyl compound, the triethyl orthoformate and the amine compound is (0.5-1.5): (0.5-1.5).
The molar ratio of the dicarbonyl compound to the triethyl orthoformate to the amine compound is 1:1: 1.
The molar ratio of the dicarbonyl compound to the triethyl orthoformate to the amine compound is 1:1.25: 1.
The dicarbonyl compound is 3- (2-halogenated phenyl) -3-oxo-ethyl propionate.
The dicarbonyl compound is 3- (2-fluorophenyl) -3-oxo-ethyl propionate.
The two compounds are aniline, pyridylamine or alkylamine.
The efficient and environment-friendly preparation of the quinolone compound is that three raw materials are put into a reactor to react for 6-48 hours at the temperature of 90-150 ℃ under the condition of no solvent and no catalyst to obtain the target quinolone compound.
And after the reaction is finished, a decompression suction filtration washing step is also included.
The decompression suction filtration washing is decompression suction filtration washing by adopting ethyl acetate, petroleum ether and methanol.
The decompression suction filtration washing is to wash for 1-3 times by using a mixed washing agent of ethyl acetate and petroleum ether with the volume ratio of 1:1 and 3-5 times of the reaction product, and then wash for 1-2 times by using a methanol solution with the volume ratio of 3-5 times of the reaction product.
The purity of the carbostyril compound product prepared by the method for efficiently and environmentally preparing the carbostyril compound can reach more than 98.9 percent.
The structural general formula of the target quinolone compound is as follows:
Figure DEST_PATH_IMAGE008
wherein R is1Is alkyl or aryl such as hydrogen, halogen, methyl, ethyl, tertiary butyl, methoxy, trifluoromethyl, cyano, nitro and the like, R2Hydrogen, aryl such as phenyl and pyridine, or alkyl such as methyl, ethyl and cyclopropyl.
The technical route for preparing the quinolone compound in an efficient and environment-friendly way is as follows:
Figure DEST_PATH_IMAGE010
the invention is further illustrated by the following specific examples:
the specifications of the materials or reagents used in the examples of the present invention and the measuring instrument are commercially available unless otherwise specified.
A nuclear magnetic instrument: bruker Avance III 400MHz nuclear magnetic instrument
An infrared spectrometer: thermo Nicolet S10 FT-IR infrared spectrometer
Mass spectrometry: agilent LC/MSD TOF instrument mass spectrometer
Melting point apparatus: beijing Taike Tech X-5 melting point instrument
Example 1
Examples the reaction formula is as follows:
Figure DEST_PATH_IMAGE012
the preparation method comprises the following steps:
firstly, under stirring, using dicarbonyl compounds, triethyl orthoformate and aniline as raw materials, putting the three components into a reactor together, heating to 130 ℃, keeping the temperature, reacting for 24 hours, stopping the reaction after a large amount of solids are separated out, and obtaining the quinolone compound after the reaction is completed. And (3) carrying out vacuum filtration, washing with petroleum ether and ethyl acetate, washing with methanol, and drying to obtain the quinolone compound.
The carbostyril compound prepared by changing the amine compound in the examples has the following yield:
Figure DEST_PATH_DEST_PATH_IMAGE013
Figure DEST_PATH_DEST_PATH_IMAGE015
Figure DEST_PATH_DEST_PATH_IMAGE017
the nuclear magnetic spectrum of the compound is shown in figures 1-13, and the compound data are as follows:
Ethyl 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylate (1):Pale-pink solid; yield 84%; m.p. 208-209 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ 8.46 (s, 1H), 8.30 (d, 1H, J = 7.72 Hz), 7.68 (s, 5H), 7.49 (t, 1H, J = 7.20 Hz), 7.39 (s, 1H), 6.98 (d, 1H, J = 8.40 Hz), 4.21 (t, 2H, J = 6.80 Hz), 1.28-1.18 (m, 3H); 13C NMR (100 MHz, DMSO-d 6 , ppm): δ 173.4, 164.6, 148.9, 140.8, 133.2, 130.8, 130.4, 128.1, 127.9, 126.6, 125.9, 118.4, 110.9, 60.3, 14.7; IR (KBr): v max (cm-1) 3434, 3065, 1718, 1625, 1550, 1510, 1477, 1413, 1364, 1315, 1252, 1223, 1095, 1022, 862, 771, 862, 821, 771, 645, 549; HRMS (ESI-TOF+): m/zCalcd for C18H16NO3 + [(M+H)+] 294.1125; found, 294.1122.
Ethyl 1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (2): White solid; yield 92%; m.p. 179-199 oC; 1H NMR (400 MHz, CDCl3, ppm): δ8.54 (d, 1H, J = 7.96Hz), 8.48 (s, 1H), 7.54 (t, 1H, J = 8.20 Hz), 7.49-7.41 (m, 3H), 7.33 (t, 2H, J = 8.08 Hz), 6.96 (d, 1H, J = 8.44 Hz), 4.42(q, 2H, J = 7.20 Hz), 1.40 (t, 3H, J = 7.12 Hz); 13C N MR (100 MHz, DMSO-d 6 , ppm): δ174.3, 165.5, 164.2, 161.7, 148.6, 140.6, 136.6, 136.6, 132.4, 129.5, 129.4, 128.3, 127.6, 125.3, 117.6, 117.4, 117.3, 111.5, 61.0, 14.4; HRMS (ESI-TOF+): m/z Calcd for C18H14FNO3Na+ [(M+Na)+] 334.0850; found, 334.0850.
Ethyl 1-(4-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (3): White solid; yield 90%; m.p. 171-173 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ8.51 (t, 3H, J = 5.00 Hz), 8.29 (dd, 1H, J = 1.24, 1.24 Hz), 8.02 (d, 2H, J = 8.88 Hz), 7.68-7.64 (m, 1H), 7.50 (t, 1H, J = 7.64 Hz), 7.05 (d, 1H, J = 8.48 Hz), 4.24 (q, 2H, J = 7.20 Hz), 1.26 (t, 3H, J = 7.08 Hz); 13C NMR (100 MHz, DMSO-d 6 , ppm): δ 173.5, 164.5, 148.4, 148.4, 145.9, 140.3, 133.3, 130.0, 127.8, 126.7, 126.0, 125.8, 118.2, 115.5, 60.4, 14.6; IR (KBr): v max (cm-1) 3444, 1724, 1613, 1526, 1476, 1350, 1252, 1216, 1135, 1097, 1020, 877, 767, 542; HRMS (ESI-TOF+): m/z Calcd for C18H14N2O5Na+ [(M+Na)+] 361.0795; found, 361.0788.
Ethyl 4-oxo-1-(4-(trifluoromethyl)phenyl)-1,4-dihydroquinoline-3-
carboxylate (4): White solid; yield 93%; m.p. 204-206 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ 8.53 (s, 1H), 8.28 (d, 1H, J = 7.92 Hz), 8.09 (d, 2H, J = 8.28 Hz), 7.97 (d, 2H, J = 8.16 Hz), 7.65 (t, 1H, J = 7.20 Hz), 7.49 (t, 1H, J = 7.36 Hz), 7.01 (d, 1H, J = 8.44 Hz), 4.23 (q, 2H, J = 6.80 Hz), 1.26 (t, 3H, J = 7.08 Hz); 13C NMR (100 MHz, DMSO-d 6 , ppm): δ173.5, 164.5, 148.7, 144.1, 140.5, 133.3, 129.5, 127.9, 127.9, 127.8, 126.6, 125.7, 118.3, 111.3, 60.3, 14.6; IR (KBr): v max (cm-1) 3448, 1725, 1610, 1553, 1478, 1325, 1250, 1130, 1067, 542; HRMS (ESI-TOF+): m/z Calcd for C19H15F3NO3 + [(M+H)+] 362.999; found, 362.0993.
Ethyl 4-oxo-1-(p-tolyl)-1,4-dihydroquinoline-3-carboxylate (5): White solid; yield 74%; m.p. 199-201 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ 8.42 (s, 1H), 8.29 (dd, 1H, J = 1.36, 1.40 Hz), 7.67-7.62 (m, 1H), 7.54-7.46 (m, 1H), 6.98 (d, 2H, J = 8.48 Hz), 4.22 (d, 2H, J = 6.80 Hz), 2.50-2.45 (m, 3H), 1.26 (t, 3H, J = 7.12 Hz); 13C NMR (100 MHz, DMSO-d 6 , ppm): δ 173.4, 164.6, 148.9, 141.0, 140.1, 138.4, 133.1, 131.2, 128.0, 127.8, 126.6, 125.5, 118.5, 110.9, 60.3, 21.2, 14.7; IR (KBr): v max (cm-1) 3433, 1724, 1625, 1550, 1473, 1406, 1314, 1243, 1207, 1125, 1090, 853, 769, 548; HRMS (ESI-TOF+): m/z Calcd for C19H18NO3 + [(M+H)+] 308.1281; found, 308.1275.
Ethyl 1-(4-(tert-butyl)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (6): White solid; yield 76%; m.p. 207-209 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ 8.45 (s, 1H), 8.29 (d, 1H, J = 7.76 Hz), 7.70-7.47 (m, 6H), 6.99 (d, 1H, J = 8.40 Hz), 4.23 (q, 2H, J = 6.80 Hz), 1.37 (s, 9H), 1.26 (t, 3H, J = 6.96 Hz); 13C NMR (100 MHz, DMSO-d 6 , ppm): δ 173.4, 164.5, 152.9, 149.0, 140.9, 138.3, 133.2, 127.9, 127.5, 127.5, 126.6, 125.5, 118.5, 110.8, 60.3, 14.7; IR (KBr): v max (cm-1) 3446, 1725, 1627, 1513, 1413, 1363, 1249, 1091, 1022, 764, 550; HRMS (ESI-TOF+): m/z Calcd for C22H24NO3 + [(M+H)+] 350.1751; found, 350.1746.
Ethyl 1-(2-bromophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (7): White solid; yield 82%; m.p. 183-185 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ8.48 (s, 1H), 8.30 (d, 1H, J = 7.96 Hz), 8.00 (d, 1H, J = 7.96 Hz), 7.88 (d, 1H, J = 7.72 Hz), 6.77 (d, 1H, J = 8.44 Hz), 7.73-7.61 (m, 3H), 7.50 (t, 3H, J = 7.40 Hz), 4.25 (q, 2H, J = 7.04 Hz), 1.27 (t, 3H, J = 7.08 Hz); 13C NMR (100 MHz, DMSO-d 6 , ppm): δ173.5, 164.5, 148.7, 140.2, 139.1, 134.4, 133.5, 132.7, 131.0, 130.3, 127.7, 126.7, 125.7, 122.3, 117.9, 111.7, 60.5, 14.6;IR (KBr): v max (cm-1) 3440, 1732, 1626, 1478, 1364, 1245, 1092, 810, 763, 543; HRMS (ESI-TOF+): m/z Calcd for C18H14BrNO3Na+ [(M+Na)+] 396.0029; found, 396.0021.
Ethyl 1-(3-bromophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (8): White solid; yield 85%; m.p. 267-269 oC; 1H NMR (400 MHz, F3CCOOD, ppm): δ9.17 (s, 1H), 8.69 (d, 1H, J = 8.08 Hz), 8.04 (t, 1H, J = 7.00 Hz), 7.92-7.85 (m, 2H), 7.63-7.40 (m, 4H), 4.55 (q, 2H, J = 7.20 Hz), 1.35 (t, 3H, J = 6.68 Hz); 13C NMR (100 MHz, F3COOD, ppm): δ 176.0, 169.5, 151.2, 143.8, 141.8, 140.6, 137.8, 134.1, 132.6, 131.6, 127.9, 126.9, 126.6, 122.9, 67.2, 14.4; IR (KBr): v max (cm-1) 3445, 2360, 1720, 1628, 1475, 1412, 1244, 1070, 1011, 767, 545; HRMS (ESI-TOF+): m/z Calcd for C18H14BrNO3Na+ [(M+Na)+] 396.0029; found, 396.0022.
Ethyl 1-(3-nitrophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (9): White solid; yield 88%; m.p. 291-293 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ8.63 (t, 1H, J = 2.08 Hz), 8.55 (s,1H), 8.50-8.47 (m, 1H), 8.31 (dd, 1H, J = 1.36, 1.36 Hz), 8.16-8.14 (m, 1H), 7.95 (t, 1H, J = 8.16 Hz), 7.67-7.63 (m, 1H), 7.52-7.48 (m, 1H), 7.03 (d, 1H, J = 8.36 Hz), 4.23 (q, 2H, J = 6.80 Hz), 1.26 (t, 3H, J = 7.08 Hz); 13C NMR (100 MHz, F3CCOOD, ppm): 176.6, 169.6, 151.8, 151.5, 143.9, 142.0, 141.1, 135.4, 134.8, 133.0, 129.3, 128.4, 124.6, 121.5, 107.6, 67.5, 14.6; IR (KBr): v max (cm-1) 3430, 3059, 1724, 1608, 1530, 1476, 1348, 1312, 1250, 1095, 930, 763, 673, 540; HRMS (ESI-TOF+): m/z Calcd for C18H14N2O5Na+ [(M+Na)+] 361.0795; found, 361.0794.
Ethyl 4-oxo-1-(m-tolyl)-1,4-dihydroquinoline-3-carboxylate (10): White solid; yield 71%; m.p. 209-212 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ8.43 (s, 1H), 8.29 (dd, 1H, J = 1.44, 1.44 Hz), 7.68-7.63 (m, 1H), 7.56 (t, 1H, J = 7.48 Hz), 7.50-7.43 (m, 4H), 6.99 (d, 1H, J = 8.44 Hz), 4.24 (q, 2H, J = 6.80 Hz), 2.42 (s, 3H), 1.26 (t, 3H, J = 7.08 Hz); 13C NMR (100 MHz, DMSO-d 6 , ppm): δ173.4, 164.6, 148.8, 140.8, 140.7, 133.1, 131.0, 130.5, 128.4, 127.9, 126.6, 125.5, 125.0, 118.5, 110.9, 60.3, 21.2, 14.7; IR (KBr): v max(cm-1) 3448, 1725, 1627, 1551, 1480, 1362, 1252, 1090, 763, 543; HRMS (ESI-TOF+): m/z Calcd for C19H17NO3Na+ [(M+Na)+] 330.1101; found, 330.1097.
Ethyl 1-(3-methoxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (11): White solid; yield 80%; m.p. 235-237 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ 8.46 (s,1H), 8.29 (d, 1H, J = 7.76 Hz), 7.69-7.47 (m, 3H), 7.31-7.21 (m, 3H), 7.03 (d, 1H, J = 8.36 Hz), 4.25 (q, 2H, J = 6.08 Hz), 3.83 (s, 3H), 1.27 (t, 3H, J = 6.84 Hz); 13C NMR (100 MHz, DMSO-d 6 , ppm): δ 173.4, 164.6, 161.0, 148.8, 141.8, 140.8, 133.2, 131.5, 127.9, 126.5, 125.5, 119.9, 118.5, 116.4, 113.6, 110.8, 60.3, 56.1, 14.7; IR (KBr): v max (cm-1) 3442, 1725, 1605, 1477, 1364, 1341, 1266, 1230, 1093, 762, 552; HRMS (ESI-TOF+): m/z Calcd for C19H14NO4Na+ [(M+Na)+] 346.1050; found, 346.1046.
Ethyl 1-(3,4-difluorophenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (12): White solid; yield 83%; m.p. 234-236 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ 8.49 (s,1H), 8.27 (d, 1H, J = 6.24 Hz), 7.99 (s, 1H), 7.77-7.49 (m, 4H), 7.04 (d, 1H, J = 7.88 Hz), 4.22 (d, 2H, J = 6.80 Hz), 1.26 (t, 3H, J = 6.84 Hz); 13C NMR (100 MHz, DMSO-d 6 , ppm): 173.5, 164.6, 148.9, 140.9, 137.2, 133.2, 127.8, 126.5, 126.0, 125.6, 119.4, 118.8, 118.4, 111.2, 60.3, 14.7; IR (KBr): v max (cm-1) 3441, 3036, 1724, 1609, 1516, 1478, 1319, 1212, 1093, 1025, 911, 863, 766, 582; HRMS (ESI-TOF+): m/z Calcd for C18H13F2NO3Na+ [(M+Na)+] 352.0756; found, 352.0750.
Ethyl 4-oxo-1-(pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylate (13): White solid; yield 62%; Mp 235-242 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ 8.86 (t, 2H, J = 6.14 Hz), 8.55 (s, 1H), 8.30 (dd, 2H, J = 7.76, 7.64 Hz), 7.75-7.65 (m, 2H), 7.51 (t, 1H, J = 7.40 Hz), 6.97 (d, 1H, J = 4.36 Hz), 4.24 (q, 2H, J = 6.80 Hz), 1.27 (t, 3H, J = 6.96 Hz); 13C NMR (100 MHz, DMSO-d 6 , ppm): δ 173.5, 164.6, 151.2, 149.1, 140.9, 137.6, 136.4, 133.3, 127.8, 126.6, 125.7, 125.3, 118.3, 114.4, 60.4, 14.7; IR (KBr): v max (cm-1) 3449, 1725, 1611, 1478, 1417, 1363, 1251, 1093, 1026, 766, 543; HRMS (ESI-TOF+): m/z Calcd for C17H15N2O3 + [(M+H)+] 295.1077; found, 295.1080.
example 2
Examples the reaction formula is as follows:
Figure DEST_PATH_IMAGE020
the preparation method comprises the following steps:
firstly, under stirring, using dicarbonyl compounds, triethyl orthoformate and amines as raw materials, putting the three components into a reactor together, heating to 130 ℃, keeping the temperature, reacting for 24 hours, stopping the reaction after a large amount of solids are separated out, and obtaining the quinolone compound after the reaction is completed. And (3) carrying out vacuum filtration, washing with petroleum ether and ethyl acetate, washing with methanol, and drying to obtain the quinolone compound.
The carbostyril compound prepared by changing the amine compound in the examples has the following yield:
Figure DEST_PATH_IMAGE022
the nuclear magnetic spectrum of the compound is shown in fig. 14-16, and the compound data are as follows:
Ethyl 6,7-difluoro-1-(4-fluorophenyl)-4-oxo-1,4-dihydroquinoline-3-
carboxylate（1）White solid; yield 94%; m.p. >300 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ 8.45 (s, 1H), 8.07 (t, 1H, J = 8.96 Hz), 7.78 (s, 2H), 7.53 (t, 2H, J = 8.00 Hz), 7.04-6.99 (m, 1H), 4.20 (d, 2H, J = 6.76 Hz), 1.24 (t, 3H, J = 6.64 Hz); 13C NMR (100 MHz, DMSO-d 6 , ppm): δ 172.0, 164.2, 161.7, 149.7, 138.4, 136.8, 130.5, 130.4, 125.1, 117.9, 117.7, 114.2, 114.0, 110.8, 107.9, 107.9, 60.5, 14.6;HRMS (ESI-TOF+): m/z Calcd for C18H12F3NO3Na+ [(M+Na)+] 370.0661; found, 370.0662.
Ethyl 1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate （2）White solid; yield 60%; m.p. >300 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ8.48 (s, 1H), 8.16-8.04 (m, 2H), 4.22-4.21 (m, 2H), 1.27 (s, 4H) 1.10 (s, 2H)；HRMS (ESI-TOF+): m/z Calcd for C15H13F2NO3Na+ [(M+Na)+] 293.0863; found, 298.0863.
Ethyl 1-ethyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate （3）White solid; yield 72%; m.p. >300 oC; 1H NMR (400 MHz, DMSO-d 6 , ppm): δ8.72 (s, 1H), 8.12-8.05 (m, 2H), 4.42 (t, 2H, J = 6.76 Hz), 4.39-4.22 (m, 2H), 4.04-4.00 (m, 2H), 1.99 (s, 3H); δ 170.8, 164.8, 149.9, 110.5, 110.3, 60.74, 60.22, 48.9, 21.2, 14.75;HRMS (ESI-TOF+): m/z Calcd for C14H13F2NO3Na+ [(M+Na)+] 281.0863; found, 281.0862。

Claims (5)

1. a method for preparing quinolone compounds in an efficient and environment-friendly manner is characterized in that dicarbonyl compounds, triethyl orthoformate and amine compounds in a molar ratio of (0.5-1.5) - (0.5-1.5) are used as raw materials, and the three raw materials are put into a reactor to react for 6-48 hours at the temperature of 90-150 ℃ under the condition of no solvent and no catalyst to obtain target quinolone compounds;
the structural formula of the quinolone compound is as follows:
Figure DEST_PATH_IMAGE001
，
the structural formula of the dicarbonyl compound is as follows:
Figure DEST_PATH_IMAGE002
，
the amine compound is R2-NH2；
Wherein: r1Is hydrogen, halogen, methyl, ethyl, tert-butyl, methoxy, trifluoromethyl, cyano or nitro; r2Is phenyl, pyridine, methyl, ethyl or cyclopropyl.
2. A process according to claim 1, characterized in that the molar ratio of dicarbonyl compound, triethyl orthoformate and amine compound is 1:1: 1.
3. A process according to claim 1, characterized in that the molar ratio of dicarbonyl compound, triethyl orthoformate and amine compound is 1:1.25: 1.
4. The method of claim 1, further comprising a washing step after the reaction is completed by suction filtration under reduced pressure.
5. The method according to claim 4, wherein the washing by suction filtration under reduced pressure is washing by suction filtration under reduced pressure using ethyl acetate, petroleum ether and methanol.
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